Headaches that accompany intracranial pathologies as well as the headache of migraine are thought to result from mechanically or chemically induced activation or sensitization of sensory nerve fibers in the intracranial meninges. However, further understanding of the mechanisms of headaches is limited by the lack of information regarding the response properties of meningeal sensory fibers. The long-term goal of this research is to identify the types of stimuli and physiological conditions that excite meningeal primary afferent neurons and to investigate the pharmacological mechanisms by which their excitation may be suppressed. Five Specific Aims are proposed to examine the responses of both pial and dural afferents. Specific Aim 1 will characterize the physiological response properties of sensory afferents supplying the middle cerebral artery using graded mechanical and chemical stimuli. Specific Aim 2 will determine the effects of increased intracranial pressure and inflammation on the response properties of meningeal afferents that innervate the dural venous sinuses and middle cerebral artery. Specific Aim 3 will determine the effects of 5HT1B/D agonists on mechanical- and chemical-induced sensitized meningeal afferents. Specific Aim 4 will determine the effects of selective calcium channel blockers on mechanical- and chemical-induced sensitized meningeal afferents. Specific Aim 5 will determine the effects of acute spreading depression on mechanical- and chemical-induced sensitized meningeal afferents.